The long-term goal of this proposal is to increase knowledge of the genetic basis of susceptibility to insulin-dependent diabetes mellitus (IDDM) by 1) refining understanding of the well-known association with HLA, and 2) investigating the role of other genes that may confer susceptibility or help maintain diabetes susceptibility genes in the population. The specific aims include three related studies. First, in order to shift to the most basic level of genetic information, nucleotide sequences will be obtained for highly variable regions of HLA-DR and DQ beta chains. Variant nucleotide sequences associated with HLA-DR3, DR (and rarely DR2) will be identified, and the frequency of these variants, which define subtypes of the DR specificities, will be determined in a large number of patients and controls. The subtypes that occur most frequently in HLA haplotypes will be tested for association with IDDM. Second, restriction fragment polymorphisms will be detected with probes for the beta chain of the T-cell receptor. These will be used to determine 1) whether germ-line variation in the T-cell receptor is associated with IDDM, separately or in interaction with HLA, and 2) whether susceptibility to IDDM is linked to genes for the T-cell receptor. Third, cloned genes for the mouse t-complex will be used to identify homologous human sequences and determine whether they are linked to HLA, associated with particular HLA specificities, and associated with IDDM. Fourth, the final organization and publication of the international IDDM - Genetic Analysis Workshop will be carried out. Techniques of molecular genetics will be used to achieve these aims. The DNA sequencing will be made possible by using the "polymerase chain reaction" to amplify nucleotide sequences of interest. The genes for the T-cell receptor and human homologues of the t-complex will be studied using cloned fragments and Southern blotting to identify closely linked restriction fragment polymorphisms. Methods of family and population genetic analysis will be used to assess the results statistically.